The worldwide burden of malaria disease is profound. Infection with the Plasmodium falciparum species has the most devastating effect, causing the death of nearly one million African children each year. Even so, malaria control is a realistic goal, based on two lines of evidence: 1) natural immunity emerges with age in persons repeatedly exposed to the parasite; and 2) pre-erythrocytic vaccine candidates can reduce incidence of clinical disease. Currently, a major hindrance in achieving this goal is the lack of a deep understanding of the mechanisms of immune protection against malaria that can guide rational vaccine design. In this project we propose two Specific Aims that will use a comprehensive systems biology approach to broaden the immunologic knowledge base of malaria by investigating naturally acquired immunity and vaccine-induced protection in African populations living in malaria-endemic areas. In Aim 1, we will determine the distinct immune signatures associated with control of parasitemia and acquired immunity in Ugandan children and adults. In Aim 2, we will partner with investigators in the conduct of a phase III RTS,S/AS01E vaccine licensure trial to define the immunogenicity and correlates of vaccine protection in young children. As relatively new investigators in this exciting research field, we will contribute our collective expertise in the design and conduct of comprehensive immunologic studies in large-scale international vaccine studies in concert with advanced systems biology, bioinformatics and network analyses. Our Seattle colleagues with recognized leadership in the malaria field will guide our efforts, and we can efficiently build upon findings in the two interactive projects. We envision these investigations will lend significant insight into the innate and adaptive immune mechanisms that control malaria infection.